22 March 2001. The abnormal form of the protein huntingtin may exert
its toxic effects on neurons in Huntington's disease by interfering with
a protein essential for gene transcription, according to a study
published in this week's issue of Science. Researchers at Johns Hopkins
University and their collaborators at Niigata University in Japan were
intrigued by evidence that CREB binding protein (CBP) was found inside
the aggregates of mutant huntingtin that collect in the neurons of
Huntington's disease patients. CREB-mediated transcripton-and CBP in
particular-promote the survival of mature cells. In the present study,
they found that the sequestering of CBP by the abnormal huntingtin
depletes the protein from its usual location in the nucleus. This was
the case in an HD cell culture model, in HD transgenic mice, and in
human HD postmortem brain. The researchers further showed that it is
specifically the polyglutamine repeats in abnormal huntingtin that
interfere with CBP-activated gene transcription and that the resultant
cell toxicity can be reversed if CBP is overexpressed in the cells.
(Overexpression of CBP also rescued cells from atrophin-1 toxicity.
Similar to huntingtin, polyglutamine repeats in this protein lead to a
rare neurodegenerative disorder.)
In the model that these results suggest, write the authors, "it is not
the [huntingtin] inclusions or aggregations that are directly toxic, but
rather the indirect effect on other proteins such as CBP." Obviously,
this interaction between abnormal huntingtin and other proteins
represents a potential therapeutic target.-Hakon Heimer.
Reference:Nucifora FC Jr, Sasaki M, Peters MF, Huang H, Cooper JK, Yamada M, Takahashi H, Tsuji S, Troncoso J, Dawson VL, Dawson TM, Ross CA. Interference by huntingtin and atrophin-1 with cbp-mediated transcription leading to cellular toxicity.
Science. 2001 Mar 23;291(5512):2423-8. Abstract